QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, October 7, 2009, 29(40):12467-12476; doi:10.1523/JNEUROSCI.3180-09.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gersten, M. Articles by Fox, H. S. PubMed PubMed Citation Articles by Gersten, M. Articles by Fox, H. S.

 Previous Article  |  Next Article 

Neurobiology of Disease
An Integrated Systems Analysis Implicates EGR1 Downregulation in Simian Immunodeficiency Virus Encephalitis-Induced Neural Dysfunction

Merril Gersten,¹ Mehrdad Alirezaei,³ Maria Cecilia Garibaldi Marcondes,³ Claudia Flynn,³ Timothy Ravasi,² Trey Ideker,^1,2 and Howard S. Fox^3,4

¹Bioinformatics Program and ²Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, ³Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037, and ⁴Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198

Correspondence should be addressed to Howard S. Fox, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800. Email: hfox{at}unmc.edu

Human immunodeficiency virus (HIV)-associated dementia (HAD) is a syndrome occurring in HIV-infected patients with advanced disease that likely develops as a result of macrophage and microglial activation as well as other immune events triggered by virus in the central nervous system. The most relevant experimental model of HAD, rhesus macaques exhibiting simian immunodeficiency virus (SIV) encephalitis (SIVE), closely reproduces the human disease and has been successfully used to advance our understanding of mechanisms underlying HAD. In this study we integrate gene expression data from uninfected and SIV-infected hippocampus with a human protein interaction network and discover modules of genes whose expression patterns distinguish these two states, to facilitate identification of neuronal genes that may contribute to SIVE/HIV cognitive deficits. Using this approach we identify several downregulated candidate genes and select one, EGR1, a key molecule in hippocampus-related learning and memory, for further study. We show that EGR1 is downregulated in SIV-infected hippocampus and that it can be downregulated in differentiated human neuroblastoma cells by treatment with CCL8, a product of activated microglia. Integration of expression data with protein interaction data to discover discriminatory modules of interacting proteins can be usefully used to prioritize differentially expressed genes for further study. Investigation of EGR1, selected in this manner, indicates that its downregulation in SIVE may occur as a consequence of the host response to infection, leading to deficits in cognition.

---

Received July 3, 2009; accepted Aug. 11, 2009.

Correspondence should be addressed to Howard S. Fox, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800. Email: hfox{at}unmc.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help